AD (Alzheimer’s disease)Aβ therapies in clinical development,

98–199β-secretase, 201–202drugs, 202–203early-phase, 204–205γ-secretase modulators, 200–201phase 2, 205–208phase 3, 208–211regulatory phase, 211–212vaccination, 199–200

alternative model, 7–9animal testing, 45, 199

canines, 163–167mice, 7, 161–163, 188nonhuman primates, 167–168

as cellular dependence inbalance, 3–4clinical and physiological hallmarks, 36defi ned, 36, 177, 217preclinical testing, 159–169projected growth of, by 2050, 1, 197as state of altered dependence, 6structural abnormalities, 15

ADAM-9, 37-10, 1, 37-17, 37

ADAS-cog (Alzheimer’s Disease Assessment Scale-cog), 197, 200, 211

ADCS (Alzheimer’s Disease Cooperative Study), 201, 212

ADME (adsorption, distribution, metabolism, excretion), 35, 177–193

optimized, 180–188GlaxoSmithKline, 184–188Merck, 181–184

in vivo effi ciency, 188–193ADNI (Alzheimer’s Disease Neuroimaging

Initiative), 207, 212–213

INDEX

243

adsorption, distribution, metabolism, excretion. See ADME

AIDS, 29, 178Alzheimer’s disease. See ADAlzheimer’s Disease Assessment Scale-cog.

See ADAS-cogAlzheimer’s Disease Cooperative Study.

See ADCSAlzheimer’s Disease Neuroimaging

Initiative. See ADNIAmgen, 20, 88amyloid cascade, 217angiotensinogen, 22antibody

anti-APP β-site, 221–223interference, 223–226

in animal models, 226–228nontransgenic mice, 226–227Tg2576, 227–228transgenic mice, 227

mAb 6E10, 24mAb 22C11, 24mAb BBS1, 223–226monoclonal, 223polyclonal, 223

AP (aspartyl protease), 18, 21, 123AA, 37–38AD, 37–38Asp2. See BACEcatalytic mechanism, 39–40classifi cation, 37–38inhibition, 41–42kinetic mechanism, 40–41memapsin 1. See BACE2memapsin 2. See BACEobstacles to inhibitors development, 29presenilin, 123–124substrate specifi city, 42–45

apoptosis, 3

BACE: Lead Target for Orchestrated Therapy of Alzheimer’s Disease, Edited by Varghese JohnCopyright © 2010 John Wiley & Sons, Inc.

244 INDEX

APP (β-amyloid precursor protein), 1, 3–4, 15–17, 159, 160, 180, 218. See also MBP; mutation

695-residue variant, 14, 23, 221, 227751-residue variant, 16770-residue variant, 36, 221–222APLP1, 42APLP2, 220C83, 15, 18, 22–23C89, 37C99, 5, 37, 159mutations, 9neo, 4N-terminal, 5, 131, 159processing, 36–37residues 657–664 of human, 4sAPPα, 5, 7, 20, 24, 159, 226, 227sAPPβ, 2, 4, 5, 9, 20, 24, 25, 220small molecules that block β-site

cleavage, 228–229Swedish (Sw), 16, 20, 22, 43, 51, 138,

218, 223, 225, 226–228EVNL/DAEF, 70KM-NL, 23–25

Type I, 16wild type (Wt), 20, 22, 43, 218, 220,

225aromatics (2EWY), 139Asp2. See BACE1asparagine

132, 19151, 19202, 19333, 19

Astellas Pharma, 72Astex Therapeutics, 108, 144

Library of Available Substances, 149AstraZeneca, 108ATLAS (Astex Therapeutics Library of

Available Substances), 149atrophy, dentate gyral, 5Automated Ligand Identifi cation

System, 75

BACE (β-site APP cleaving enzyme), 1, 36, 159, 177, 219, 229. See also enzyme

1, 218–219, 220, 221, 2262, 219

memapsin 1, 24, 29, 37Asp2, 23, 24, 25, 123

assaybiological, 35–55enzyme, 53inhibitors screening, 50–53protein, 54–55

cleavagecaspace cleavage, and neuronal trophic

dependence, 4–5dependence receptors, and AD

pathology, 5–9as a molecular switching

mechanism, 2–3downstream pathways, 5γ-, 16, 20inhibitors, 59–94

assay strategies, 45–46memapsin 2, 18, 26, 123preparation, 126–135

in E.coli, 129–130soluble derivitives, 127–128

protein overview, 18–21structure, 38–39validation of, 27

Bateman, R. J., 201Baxter, E. W., 131BBB (blood–brain barrier), 125, 160–161,

166–167, 177–180, 205benzyl carbamates (2HIZ), 139bepineuzimab, 206β-amyloid precursor protein. See APPβ-site APP cleaving enzyme. See BACEBiacore, 108biomarkers, 15–16, 206–207blood–brain barrier. See BBBbond

Ala-Thr, 16Arg-Arg, 18Asp-Ala, 70Asp–Lys, 24Asp-Thr/Ser-Gly, 18, 23Ile-Ala, 72–73Lys-Leu, 24, 37Met-Asp, 16Phe-Ala, 24, 37Phe-Phe, 24, 37Phe-Val, 19Tyr-Glu, 16Val-Ile, 16Val-Met, 72–73

bridge, disulfi de, 26

INDEX 245

Bristol-Myers Squibb (BMS), 85–87Bruinzeel, W., 128Buck Institute, 229

CAA (cerebrovascular amyloid angiopathy), 166–167

Caenorhabditis elegans, 2, 23Cafl isch, A., 145calculated molar refractivity. See CMRcaspase

apical, 3-6, 1, 5, 7-8, 1, 3–4, 7-9, 3

cDNA2256 bp, 20

cellCOS-7 APP751, 25death

factors inducing programmed, 2neuronal, 7

MDCK, 219Neuro-2A, 24neuroblastoma

IMR-32, 24Schwann, 28SH-SY5Y APP695, 23

central nervous system. See CNScerebral hemorrhagic syndrome, 9cerebrospinal fl uid. See CSFcerebrovascular amyloid angiopathy. See

CAAchemistry, computational, 47, 116,

125–126, 145affi nity binding predictions, 146brain penetration modeling, 147–148protonation states and impact, 148selectivity assessment, 146–147virtual screening

combination, 149–150fragment-based, 149ligand-based, 148–149

Chinese hamster ovary. See CHOCHO (Chinese hamster ovary), 128, 221chromosome 11q23–24, 23CIBIC (Clinician’s Interview Based

Impression of Change-plus), 197, 211

Clinician’s Interview Based Impression of Change-plus. See CIBIC

CMR (calculated molar refractivity), 186–187

CNS (central nervous system), 28, 205

collagen, types I and IV, 6CoMentis, 72, 94, 192CoMentis/Astellas, 202computerized tomography. See CTcrystallization, 125–126, 127CSF (cerebrospinal fl uid), 206, 208–210CT (computerized tomography), 206

D664A, 5Dab, 6DAD, 200DCC (detected in colorectal cancer),

2–3DELFIA technology, 229detected in colorectal cancer. See DCCdisease modifi cation, 198DR6 (death receptor 6), 4–5Drosophila, 51–52DSM-IV-TR criteria, 209dysfunction, synaptic, 2

Elan, 21–22, 59–70Eli Lilly, 72–74endoplasmic reticulum (ER). See ERendothiapepsin, 118enzyme. See also BACE

alkaline phosphatase (AP), 49–50Asp1, 23, 24, 51Asp3, 23Asp4, 23Asp664, 5CYP3A4, 168glycosylation, 220liver cytochrome P450

CYP3A4, 178, 190pepsin, 26renin, 29sialyl-transferase ST6Gal I, 220

EPSP (excitatory postsynaptic potential), 5ER (endoplasmic reticulum), 220–221Escherichia coli (E. coli), 21, 26, 108, 127,

129–130, 131EST (expressed sequence tag), 23

AA136368, 26AA207232, 26R55398, 26

246 INDEX

excitatory postsynaptic potential. See EPSP

expressed sequence tag. See EST

Fe65, 6FEP (free-energy perturbation), 146FlexX, 148

Pharm, 148fl uorescence resonance transfer. See FRETFlurbiprofen, 124Flurizan, 203fMRI (functional magnetic resonance

imaging), 207–208free-energy perturbation. See FEPFRET (fl uorescence resonance

transfer), 49, 221F-spondin, 6functional magnetic resonance imaging. See

fMRI

GlaxoSmithKline, 80–82glycosylation, 127

N-linked, 19glypican, 6Golgi/endoplasmic reticulum, 18, 25. See

also TGN

HBA (H-bond acceptors), 81H-bond acceptors. See HBAHE (hydroxyethylene) isostere, 70, 74, 80,

136, 136–137, 180HEA (hydroxyethylamine) isostere, 61,

85–86, 87–88, 136, 136–137, 180HEK293 (human embryonic kidney)

cells, 20–21, 51, 59, 108, 128clone, 23–24

high-pressure liquid chromatography. See HPLC

high-throughput screening. See HTSHMC (hydroxymethylcarbonyl

isostere), 88–89HPLC (high-pressure liquid

chromatography), 44, 47, 50HTS (high-throughtput screening), 35, 59,

77, 90, 107, 143, 180hydroxyethylamine isostere. See HEAhydroxyethylene isostere. See HEhydroxymethylcarbonyl isostere. See

HMChypertension, 29, 178

hypomyelination, 28hypothesis, amyloid cascade, 1

IL-R2 (interleukin-1 receptor II), 45imaging. See also CT; fMRI; MRI; PET

amyloid plaque, 207inhibition

competitive, 41noncompetitive, 42uncompetitive, 42

inhibitorsacetamide, 88aminoquinolines to

aminopyridines, 112–116anti-amyloid, 198assay

capture (CA), 48chemiluminescence (CL), 49–50electrochemiluminescence

(ECL), 49–50fl uorescence polarization (FP),

48–49fl uorescence resonance transfer, See

FRETHPLC, 50strategies, 46–48time-resolved-FRET (TR-FRET), 49

BACE, 197–213novel, 217–230

BACE1, 160–161benzamide, 88biophysical, 108–110Compound 1, 109–110Compound 2, 109Compound 3, 110–111Compound 4, 111Compound 5, 111, 181–183Compound 6, 111, 181Compound 7, 111, 183Compound 8, 111–112

TC-1, 183, 190–191Compound 9, 116, 183Compound 10, 116, 184Compound 11, 116Compound 12, 116

(GSK188909), 186, 188–189Compound 13, 116–117, 184–186Compound 14, 116–117, 184Compound 15, 117, 187Compound 16, 118

INDEX 247

Compound 17, 118Compound 18, 118Compound 19, 118Compound 20, 118–119Compound 71, 77–77Compound 86, 83Compound 87, 83–84Compound 90, 85Compound 91, 86–87Compound 93, 86Compound 94, 87Compound 97 (NB-544), 87Compound 98 (NB-533), 87Compound 108 (KMI-429), 89Compound 109 (KMI-758), 89Compound 110 (KMI-1283), 89Compound 111 (WY-25105), 90–91Compound 115 (WY-24454), 90–91Compound 120 (WY-258131), 92–93CTS-21166, 29, 72, 192CTS-21166 (ASP1702), 202fragment screening

advantages and disadvantages, 107approaches, 107–121rules, 107

GF120918, 189, 191–192glutamic acid, 139GRL-8234, 71GSK188909, 81hydrazones, 111–112identifi ed, 110imidazolidinone 89, 84isocytosines to dihydroisocysteines,

117–119isophthalimide, 86Kunitz, 16LY-450139, 124, 200–201, 205macrocyclic, 61–62morpholine, 74neuroprotective, 198nonpeptidomimetic, 141–142

acylguanidines, 143carbenimines, 142–143dihydroaminoquinazolines, 144–145

OM-99, 111OM-99–2, 70–71, 108, 139, 146, 148,

180oxirane, 88peptidomimetics, 135–138

piperazinone/imidazodinone, 141

piperidine, 141pyrrolidine, 141

phenyureas, 111piperidine, 74, 82–83piperizinone 88, 84prodrug HEA, 61–63pyridone, 88pyrrolidine, 74, 82–83, 86renin, 138structure-based drug design,

123–151tertiary carbinamine, 167–168

TC-1, 168tyramines, 116–117WAY-258131, 192

interdependence, synaptic element, 7interleukin-1 receptor II. See IL-R2isophthalate (2IQG), 139isostere. See HE; HEA; HMC; TSI

KAI1, 6kinase, tyrosine, 2Kyoto Pharmaceutical University/University

of Tokyo, 88

laminin, 6–7lanthanides, 49LIE (linear interaction energy), 146ligand, trophic, 3Limongelli model, 148–149linear interaction energy. See LIElipoprotein receptor-related protein. See

LRPlong-term potentiation. See LTPloss

neuronal, 2, 160synaptic, 2

LRP (lipoprotein receptor-related protein), 45

LTP (long-term potentiation), 5

magnetic resonance imaging. See MRImaltose-binding protein. See MBPMAP system, 222–225MBP (maltose-binding protein). See also

APPAβ, 3, 5, 9, 15–16, 16–17, 20, 159

1–40, 161–42, 1, 16amyloidogenicity, 16–17

248 INDEX

MBP (maltose-binding protein) (cont’d)as “antitrophin,” 6derivation of, 1-40, 16, 221-42, 16, 218, 220–221, 230

C-26, 21C-83, 15, 18, 22–23C-89, 20C-99, 20, 21C-125, 21, 22multimerization, Aβ-induced, 5

MC (Monte Carlo) simulations, 146MCI (mild cognitive impairment), 1MD (molecular dynamics), 146memapsin 2. See BACE1Merck, 74–80, 229methionine 35, 4mice

knockout, 27–28PDAPP transgenic, 28, 161–163

Michaelis-Menten model, 40–41mild cognitive impairment. See MCIMMSE, 200molecular dynamics. See MDMonte Carlo simulations. See MCMRI (magnetic resonance imaging), 200,

206, 210mutation. See also APP

affecting Aβ processing, 9Arctic, 9D664A, 7

National Center for Biotechnology Information. See NCBI

NCBI (National Center for Biotechnology Information), 26

neoepitope, 4NeoGenesis, 75neogenin, 2–3neophobia. See LTPnetrin, 7

-1, 6neurodegeneration, 2–3, 199neurons, cholinergic, 217Neuropsychological Test Battery. See

NTBneurotransmitters, 7

acetylcholine, 197cholinesterase, 197

NINCDS-ADRDA criteria, 209

NMR, 107Novartis, 87–88NRG1 (type III neuregulin1), 220NTB (Neuropsychological Test

Battery), 200

Oklahoma Medical Research Foundation (OMRF), 25–26, 70–72

oligodendrocytes, 281FKN, 140oxyacetamide, 143

p21-activated kinase. See PAKPAK, 5Patched, 3PDB (protein data bank), 131PDGF-B (platelet-derived growth

factor-B), 5peptide

Aβ, 36, 217, 220–221. see APPAICD, 7AN1792, 199biomarkers, 15C31, 9GLTNIKTEE ISEISY-EVEFRWKK, 44,

50Jcasp, 9LB83190, 51–52LB83192, 51–52LB83202, 51–52p3, 7P10-P4’ (Stat-Val), 22SEISY-EVEFRWKK, 44, 50

peripheral nervous system. See PNSpermeability glycoprotein. See P-gpPET (positron emission tomography), 207,

210P-gp (permeability glycoprotein), 29Pharmacia, 22–25Pharmacia (Pfi zer), 59–70pharmacokinetic profi le. See PKPK (pharmacokinetic profi le), 177plaques, neuritic, 15, 36, 159, 199, 217platelet-derived growth factor-B. See

PDGF-BPNS (peripheral nervous system), 28pockets

bindingS2 and S4, 139–140

S1-S4, 142

INDEX 249

S3, 143specifi city, 131–136

S1, 138S3, 135, 138–139

positron emission tomography. See PETpresenilin-1, 2prime side, and specifi city pockets,

140–141protease

aspartyl, 219. See APrenin, 146–147

cathepsin B, 218, 220cathepsin D (Cat-D), 18, 23, 25, 61,

74–75, 123, 139, 146–147, 219cathepsin E, 139, 219cysteine, 21HIV-, 22, 25, 29, 63, 123, 160, 178

Ritonavir, 191insulin-degrading enzyme, 37Lopinavir, 178metallo, 21napsin A, 219neprilysin, 37nexin-II, 16pepsin, 22, 123, 219peptidyl peptidases, 124renin, 22, 25, 63, 74–75, 160, 123, 178,

219Aliskiren, 178

serine, 21protein, 15

Aph1, 37, 44, 123Aph2, 44cytoskeletal tau, 160fl exibilty, 145–146hyperphosphorylated microtubule binding

tau, 4, 36natural, as BACE substrate, 46neuregulin-1 (NRG1), 28, 45nicastrin, 37, 123Notch, 124, 200Pen2, 37, 123phosporylated tau (p-tau), 208presenilin, 37, 123, 160P-selectin glycoprotein ligand-1, 220tau (t-tau), 208Type I transmembrane, 18

protein data bank. See PDBproteoglycan, heparan sulfate, 6P-selectin glycoprotein ligand 1. See PSGL-1

PSGL-1 (P-selectin glycoprotein ligand 1), 45

Ptc, 2–3pulse-chase, 205pyridyl (2HM1), 139pyrrolidinones (2VIZ), 139

radical, sulfuranyl, 4receptor

axon guidanceDCC, 9

death 6. see DR6“dependence,” 2insulin, 4neurotrophin

p75NTR, 9Research Collaboratory for Structural

Bioinformatics, 131residue

α-, 9Ala, 26Arg, 19, 44, 61, 129, 135, 139, 141,

146–147Asn, 23, 25, 44Asp, 21, 22–23, 25, 36–37, 42, 114–116,

116, 118–119, 143, 144, 145, 146, 148664, 3, 7protonated and nonprotonated, 39

β-, 9γ-, 9, 18, 24Gln, 138Glu, 18–19, 22, 36–37, 44, 134, 139Glu11, 51Gly, 19, 44, 116, 137Gyl, 134Ile, 44, 138, 140, 149Leu, 21–22, 129, 135, 138, 142Lys, 22–23, 134major, 1Met, 21, 22, 36, 44, 61Nle, 44Phe, 44, 116, 138, 149Pro, 141Ser, 19, 26, 44, 135, 143, 145Sta, 22Thr, 18–19, 26, 44, 84, 135, 139, 140, 143Trp, 138, 149Tyr, 22, 36, 116, 134, 138, 139, 141,

143, 144, 146Val, 18, 21, 44, 140

250 INDEX

RET, 2–3retraction, neurite, 2, 5, 7Roche compound collection, 108, 116“rule of fi ve,” 125

SAR (structure-activity relationships), 126, 180

SBDD (structure-based drug design), 125Schering Plough, 82–85secretase

α-, 1, 16, 37, 159, 226β-, 16–20, 36–37, 123, 124–125, 159,

160, 177, 201–202, 218, 218–220, 221–222, 225, 226. See BACE

BACE, 220γ-, 37, 123–125, 159–160, 200–201, 218.

See also BACEsequence

Arg-His5-Asp-Ser-Gly-Tyr10-Glu-Val-His-His-Gln, 22

Asn-Leu, 16DT/SGT/S, 219EVNF-EVEF, 51Gly-Tyr-Glu-Val, 43Ile-Ser-Glu-Val-Lys-Met-Asp1-Ala-Glu-

Phe-Arg-His, 22ISY-EV, 51Leu-Val-Phe-Phe-Ala-Glu-Asp, 24Lys-Met-Asp-Ala, 43SEVKM-DAEFR, 138SEVNL-DAEFR, 138

6-sialyltransferase. See ST6Gal1SmithKlein Beecham (SKB), 25Sonic hedgehog, 3ST6Gal1 (6-sialyltransferase), 45Stokes shifts, 49structure-activity relationships. See SARstructure-based drug design. See SBDDsugar, O-linked, 19sulfones (2VIY), 139sultams (2VIJ), 139Sunesis, 77surface plasmon resonance, 107–108, 116,

117

T18H9.2, 23TACE. See secretase, α-tangles, intracellular neurofi brillary, 15, 36,

159–160hyperphosphorylated tau, 217

Tarenfl urbil, 203Terminal Fragment

C-, 13183, 24–2599, 24–25

N-, 28Tessier-Lavigne, 5TGN (trans-golgi network), 125, 220–221.

See also Golgi/endoplasmic reticulum

therapiesdonepazil, 197galantamine, 197memantine, 197rivastigmine, 197

thermodynamic integration. See TITI (thermodynamic integration), 146Tramiprosate, 202–203trans-golgi network. See TGNtransition-state isostere. See TSItransport defects, axonal, 2triplets

AVE, 44EVD, 44EVE, 44TSI (transition-state isostere), 72–73, 76,

80, 136. See also HE; HEAaminoethylenes, 136statine, 136, 180

2VJ9, 140type III neuregulin1. See NRG1

Unc5H2 (uncoordinated gene 5 homologue 2), 2–3

uncoordinated gene 5 homologue 2. See Unc5H2

vapor diffusion experiment, 131Vertex pharmacophore, 148–149VGSC (voltage-gated sodium

channels), 44–45voltage-gated sodium channels. See

VGSC

Wyeth, 90–94

X-ray crystallography, 45, 107–108, 111, 116, 119, 130–135, 144